Inflammatory events play a central role in the pathology of disease conditions that adversely affect a considerable proportion of the population in developed countries. This process is mediated by cytokines, a system of polypeptides that enable one cell to signal to initiate events in another cell that initiate inflammatory sequelae. Normally, the system acts as part of a defensive reaction against infectious agents, harmful environmental agents, or malignantly transformed cells. But when inflammation exceeds the requirements of its defensive role, it can initiate adverse clinical effects, such as arthritis, septic shock, inflammatory bowel disease, and a range of other human disease conditions.
Small-molecule antirheumatic drugs such as methotrexate and sulfasalazine are insufficient to control inflammation in about two-thirds of arthritis patients. New biological agents developed in the last decade have proved to be effective for a majority of patients unresponsive to traditional drugs. The target for such agents is often one of the cytokine pathways—either capturing the ligand conveying the signal from one cell to another, or blocking the receptor at the surface of the effector cell, preventing transduction of the cytokine signal, thereby forestalling the inflammatory events.
A leading biological agent for treating inflammatory conditions is Enbrel® (Etanercept), marketed by Amgen Corp. It is a chimeric molecule comprising the extracellular portion of the human TNF receptor linked as a dimer to the IgG Fc region. The compound interferes with the binding of TNF to cell-surface TNF receptors—showing the importance of modulating the TNF pathway for clinical therapy of inflammatory conditions.
Enbrel® is licensed in the U.S. for treatment of patients with moderate to severe rheumatoid arthritis, juvenile rheumatoid arthritis, and psoriatic arthritis. Approval is expected in 2003 for treating ankylosing spondylitis. Sales of Enbrel® were $750 million in 2001. Scaling up production to meet growing demand has been a challenge. The projected sales in the U.S. market for current indication is expected to reach at least $4 billion by 2005, just for current indications.
Other biological agents currently licensed in the U.S. for treating arthritis are Remicade® (Infliximab), a chimeric antibody that binds the TNF-α ligand; Humira™, a humanized anti-TNF-α antibody, and Kineret™ (Anakinra), a recombinant form of IL-1Ra, an antagonist of the interleukin-1 receptor.
As it happens, cytokine ligands are not the only component of the cytokine pathway released from cells involved in inflammation. Receptors for the cytokines on the target effector cell are also released in certain inflammatory conditions (Gatanaga et al., Proc. Natl. Acad. Sci. USA 87:8781-8784, 1990; Brakebusch et al., J. Biol. Chem. 269:32488, 1994).
By 1997, Gatanaga and Granger had isolated a polypeptide that causes the human TNF receptor (both the p55 and p75 isoforms) to be cleaved from the cell surface (U.S. Pat. No. 6,569,664). They demonstrated that the enzyme can be used as an anti-inflammatory agent for treatment of septic shock, and proposed that it be used to treat other inflammatory conditions, such as arthritis, cachexia, and inflammatory heart disease. Subsequently, Gatanaga and Granger isolated nine recombinant cDNA clones that encoded proteins implicated in TNF receptor release (U.S. Pat. No. 6,593,456).
Some subjects having inflammatory conditions do not respond to the medicaments currently available, and the consumer cost of existing biological agents can be over $10,000 per year. There is a need for new biological agents that inhibit multiple cytokine pathways and which can be produced for more modest cost.